Of all the known diseases, heart attacks are the leading cause of death worldwide,
with strokes coming a close second.
Both are considered types of cardiovascular disease.
Due to their prevalence and lethality, treating and preventing cardiovascular diseases is
a huge priority in our healthcare system.
If you are at risk of having a heart attack or stroke, doctors will likely prescribe you
a class of drugs called statins, which decreases LDL cholesterol levels.
So what is LDL cholesterol, how do statins decrease LDL cholesterol, and why does that
decrease the risk of cardiovascular disease?
Learn more about how statins work, who should take them, and what the side effects are
in this episode of Medicurio.
In humans, cholesterol is an essential molecule used to make
steroid hormones, bile acids, and Vitamin D.
It is also a vital part of the cell membrane of each and every cell in the body.
Most of the cholesterol in our body is synthesized in the liver
and transported to other parts of the body via blood.
However, cholesterol is insoluble in blood and must be packaged within special particles
called low-density lipoprotein particles to enter the blood.
When cholesterol is within these particles, it is referred to as LDL-cholesterol.
There is generally less than 100 mg/dL of LDL-cholesterol
flowing through the blood of a healthy adult.
When the blood vessel wall is damaged due to high blood pressure, increased fats and
cholesterol in blood, high blood sugar from diabetes, or toxins from smoking, a complex
inflammatory response occurs in which plaque begins to form at the site of damage.
Plaque is a buildup of LDL cholesterol, other fats, and dead immune cells,
covered by a cap of smooth muscle cells.
What makes plaque so dangerous is that the cap can rupture, revealing the interior of
the plaque which can trigger blood clot formation and blood vessel blockage.
A heart attack occurs when blood vessels within the heart become blocked by this process.
Heart tissue supplied by those blood vessels become deprived of nutrients and oxygen
and eventually die.
The heart no longer pumps properly, fatally shutting down the body.
The same blockage could happen in the blood vessels of the brain to cause strokes, leading
to brain damage and possibly death.
Considering that LDL cholesterol is one of the main components of plaque, it is not surprising
that many studies have linked higher LDL cholesterol levels
to a higher risk of cardiovascular disease.
This prompted scientists to look for drugs that decrease LDL cholesterol levels
to prevent cardiovascular disease.
In 1971, biochemist Dr. Akira Endo and his team isolated the first statin, compactin,
from the fungus Penicillium.
Based on compactin’s early success in lowering LDL cholesterol, pharmaceutical companies
began creating structurally similar molecules with different potencies and rates of breakdown,
giving patients a wide range of statins to choose from
that will best benefit their individual situations.
The effectiveness of statins have made them one of the most highly prescribed and commercially
successful drugs in the world, with the most popular statin, atorvastatin, raking in over
$125 billion dollars worldwide since its creation in 1996.
So why are statins so effective at loweromg LDL cholesterol?
To understand how statins work, we first need to understand
how cholesterol is made in the body.
The cholesterol synthesis pathway involves multiple steps.
The most important step of the entire pathway is the formation of mevalonate from a molecule
called HMG-CoA.
HMG CoA contains Coenzyme A, which is removed to form mevalonate.
This reaction is carried out by an enzyme called HMG-CoA reductase.
It turns out that statins can also bind to this enzyme because statins and HMG-CoA have
similar structures.
However, HMG-CoA cannot bind to the enzyme if a statin is occupying that binding site,
meaning that no reaction occurs and no mevalonate can be formed.
This is how statins stop cholesterol synthesis.
So how does stopping cholesterol synthesis using statins affect LDL cholesterol levels
in the blood?
Without cholesterol synthesis, the liver now needs to look for other sources of cholesterol
to create bile and other important compounds.
The only major source of cholesterol left now is in the blood, packaged as LDL cholesterol.
To reabsorb the LDL cholesterol, liver cells begin to express LDL receptors on their surface,
which bind to LDL particles, internalizes them, and breaks them down to obtain cholesterol.
This removes LDL cholesterol from the blood, resulting in lower LDL cholesterol levels
and a lower risk of developing plaque and cardiovascular disease.
So who should take statins and what are some possible side effects?
Statins should be taken by people who are at a high risk of developing cardiovascular disease.
Though guidelines vary between healthcare systems, generally this includes people who
have very high LDL cholesterol levels above 190 mg/dL, are living with diabetes,
have a family history of cardiovascular disease, or have already had a heart attack, angina, or stroke.
Essentially, any conditions that may cause plaque to form.
As for side effects of statins, around 5 to 10% of statin users experience clinically
significant muscle pain and weakness, which understandably causes some of them to stop
taking their medication.
Although stopping stain use may relieve muscle pain, high-risk patients lose the preventative
effects of statins, possibly resulting in a lethal heart attack or stroke.
Instead, patients should discuss their pain with their doctor and perhaps switch to other
cholesterol-lowering drugs or undergo lifestyle changes, but once again, do not simply stop
taking statins without an alternative method of decreasing LDL cholesterol.
Unfortunately, the mechanism of muscle damage by statins is not well understood.
One possible explanation is that molecules produced in the cholesterol synthesis pathway
are also used to synthesize a molecule called CoQ10.
CoQ10 is involved in cellular energy production,
particularly at energy-consuming tissues such as muscles.
Inhibiting HMG-CoA reductase by statins may also be causing a decreased synthesis of CoQ10,
which might impair energy production in muscle to cause muscle pain and weakness.
Aside from this, statins are a relatively safe drug to use with proper dosage.
There is no question that statins can reduce LDL cholesterol levels as intended, and has
likely prevented countless heart attacks, strokes, and deaths worldwide.
However, the fact that statins are one of the most prescribed drug classes points to
an underlying problem in lifestyle choices that have made cardiovascular disease so common.
As a society, we should move towards becoming healthy enough to avoid statin use.
Thanks for watching, and see you next time on Medicurio.